Roles of nicotinic acetylcholine receptor beta subunits in function of human alpha4-containing nicotinic receptors.
Roles of nicotinic acetylcholine receptor beta subunits in function of human alpha4-containing nicotinic receptors.
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烟碱乙酰胆碱受体β亚基在人类含α4烟碱受体功能中的作用。
DOI：
10.1113/jphysiol.2006.114645
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发表时间：
2006
期刊：
影响因子：
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通讯作者：
Lukas,RonaldJ
中科院分区：
文献类型：
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作者：
Wu,Jie;Liu,Qiang;Yu,Kewei;Hu,Jun;Kuo,Yen-Ping;Segerberg,Marsha;StJohn,PaulA;Lukas,RonaldJ
天然表达的含有α4亚基（α4*‐nAChR）和β2亚基（α4β2‐nAChR）的尼古丁乙酰胆碱受体（nAChR）是哺乳动物大脑中最丰富、最具亲和力的尼古丁结合位点之一。β4亚基也与α4亚基在涉及尼古丁和尼古丁依赖行为反应的几个脑区域中丰富表达和共定位。因此α4β4‐nAChR也可能存在并发挥重要的功能作用。本研究测定了α4β2‐和α4β4‐nAChR在人SH‐EP1上皮细胞中的异源表达。人α4β4‐nAChR介导的全细胞电流的振幅比人α4β2‐nAChR介导的全细胞电流的振幅高4倍，并且表现出更慢的急性脱敏和功能衰竭。尼古丁激动剂在α4β4‐nAChR处诱导全细胞电流反应峰值，其功能效力通常高于α4β2‐nAChR。Cytisine和lobeline在α4β4‐nAChR中作为完全激动剂，而在α4β2‐nAChR中仅为部分激动剂。然而，除六甲铵外，烟碱拮抗剂对功能性α4β2‐和α4β4‐nAChR具有相似的亲和力。在正保持电位下，全细胞电流响应显示α4β2‐nAChR比α4β4‐nAChR向内整流更强。综上所述，这些发现表明人类nAChR β2或β4亚基可以与α4亚基结合产生两种具有不同生理和药理特征的α4*‐nAChR。α4*‐nAChR的多样性可能与神经系统功能、疾病和尼古丁依赖有关。
Naturally expressed nicotinic acetylcholine receptors (nAChR) containing α4 subunits (α4*‐nAChR) in combination with β2 subunits (α4β2‐nAChR) are among the most abundant, high‐affinity nicotine binding sites in the mammalian brain. β4 subunits are also richly expressed and colocalize with α4 subunits in several brain regions implicated in behavioural responses to nicotine and nicotine dependence. Thus, α4β4‐nAChR also may exist and play important functional roles. In this study, properties were determined of human α4β2‐ and α4β4‐nAChR heterologously expressedde novoin human SH‐EP1 epithelial cells. Whole‐cell currents mediated via human α4β4‐nAChR have ∼4‐fold higher amplitude than those mediated via human α4β2‐nAChR and exhibit much slower acute desensitization and functional rundown. Nicotinic agonists induce peak whole‐cell current responses typically with higher functional potency at α4β4‐nAChR than at α4β2‐nAChR. Cytisine and lobeline serve as full agonists at α4β4‐nAChR but are only partial agonists at α4β2‐nAChR. However, nicotinic antagonists, except hexamethonium, have comparable affinities for functional α4β2‐ and α4β4‐nAChR. Whole‐cell current responses show stronger inward rectification for α4β2‐nAChR than for α4β4‐nAChR at a positive holding potential. Collectively, these findings demonstrate that human nAChR β2 or β4 subunits can combine with α4 subunits to generate two forms of α4*‐nAChR with distinctive physiological and pharmacological features. Diversity in α4*‐nAChR is of potential relevance to nervous system function, disease, and nicotine dependence.